This proposed research concerns the mechanism of chemical carcinogenesis using rat liver and colon as target tissues. The working hypothesis of this proposal is that carcinogenesis has to be conceived as disdifferentiation of stem cells by desynchronized degradation of selected proteins. A prominent biochemical feature of developed tumors of both these models is a very high level of gamma-glutamyl transpeptidase which is also present in the fetal and neonatal homologous tissues but not during normal liver regeneration. Other important evidences corroborate this hypothesis, indicating that the origin of tumors in tissues mentioned above is in relatively less differentiated GT-ase-rich, GSH-poor cells. The main aims of this proposal are: 1.) Identification of cells from which the cancerous line originates. 2.) The problem of the basic reaction induced by carcinogen that brings the 'stem' cell on to the path of cancerous development. This concerns the changes in the degradation rates of acidic nuclear proteins as a result of, or leading to, the cancerous pathway. Three collateral secondary aims will also be followed. The methods to be used to reach these objectives will include autoradiography, isolation of normal and cancerous GT-ase in homogeneous form, preparation of antibodies and identification of original stem cells by the reaction with antibodies to cancerous GT-ase coupled with fluorescent dye and by microscopy. Isolation of nuclear acidic proteins, gel electrophoresis and immunoelectrophoresis will be used in objective 2.